PROJECT SUMMARY The overall goal of the Moffitt Cancer Center (MCC) Immunology (IMM) Program is to define the mechanisms by which tumors evade rejection by the immune system and to develop strategies to thwart them. Fundamental discoveries by IMM members have led to novel immunotherapy trials that directly benefit cancer patients. Key to the Program's success is the close integration of IMM clinical, translational, and basic scientists that facilitates rapid progression of novel immunotherapies from the bench to bedside. The goals of Specific Aim 1 are to advance and translate T-cell therapies for solid tumors and hematologic malignancies, by bringing laboratory and pre-clinical studies of the IMM Program to the patient bedside in the form of novel investigator- initiated clinical trials. Specific areas of focus include: (1) adoptive T-cell immunotherapy using ex vivo expanded tumor-infiltrating lymphocytes and genetically modified immune effector cells; (2) mechanistic strategies to improve adoptive cell therapy; (3) restoration of tumor-specific responses by immune checkpoint inhibitors, histone deacetylase inhibitors (HDACi), and vaccination; and (4) defining gene expression signatures of immune responders. MCC infrastructure that supports IMM members includes: (i) the Immunotherapy Working Group that conceives interventional trials; (ii) a Good Manufacturing Practice- compliant Cellular Therapy Core Facility; and (iii) the interdisciplinary Immune and Cellular Therapy clinical service to deliver therapy to patients. The goals of Specific Aim 2 are to define molecular and cellular mechanisms that can exploit innate and adaptive immunity against cancer. Here, IMM members seek to discover and develop molecular approaches to harness the immune system. Collaborative studies include those assessing T-cell recruitment and suppression, natural killer cell control, myeloid-derived suppressor cell expansion, and selective HDACi immune modulation. These initiatives have generated several innovative approaches that control these processes, including therapeutic translation into clinical trials. The goals of Specific Aim 3 are to prevent graft-versus-host disease (GVHD) while maintaining the potency of graft-versus- leukemia and other blood cancers following hematopoietic cell transplantation (HCT). The IMM Program has made significant impact in this arena, including the discovery that Th17 cells have a central role in the severity of GVHD and in the response to therapy. The approaches to prevent GVHD and maintain anti-tumor response include: (1) adoptive transfer of donor Tregs specific against host minor-histocompatibility antigens; (2) targeting the common IL-12/IL-23 p40 receptor chain; (3) targeting JAK2 or STAT3; and (4) defining gene expression signatures associated with operational tolerance following allogeneic HCT. The Program is composed of 25 members from 10 different academic departments. During the reporting period, 534 cancer- related articles were published, with 167 (31)% intra-programmatic and 207 (39%) inter-programmatic. Grant funding for the Program is $18.8 million, of which $7.0 million is peer-reviewed , including 43% from NCI.